In vivo metabolism and final disposition of a novel nonsteroidal androgen in rats and dogs

Drug Metab Dispos. 2006 Oct;34(10):1713-21. doi: 10.1124/dmd.106.009985. Epub 2006 Jun 30.

Abstract

Compound S-4 (S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide) is a novel nonsteroidal androgen agonist that mimics many of the beneficial pharmacologic effects of testosterone with lesser effects on the prostate. S-4 demonstrated high androgen receptor binding affinity as well as anabolic specificity during in vivo pharmacologic studies in rats, identifying it as the first member of a new class of selective androgen receptor modulators. The purpose of these studies was to determine the pharmacokinetics and metabolism of S-4 in dogs. S-4 showed linear pharmacokinetics after both intravenous (i.v.) and oral (p.o.) administrations at pharmacologically relevant doses, with a mean clearance of 4.6 ml/min/kg and a mean half-life of about 200 min. It is interesting that dose-dependent oral bioavailability was seen. However, at pharmacologically relevant doses, the oral bioavailability of S-4 was 91%. Species differences were observed in S-4 metabolism; the major metabolic pathway for S-4 in dogs was deacetylation of the B-ring acetamide group and reduction of the A-ring nitro group, whereas the major metabolic pathway for S-4 in rats was hydrolysis on the amide bond and reduction of the A-ring nitro group. In addition, oxidative metabolites and phase II metabolites were identified in both rats and dogs. These studies demonstrate that S-4 maintains its promising pharmacokinetic properties in dogs (i.e., high oral bioavailability and linear kinetics) and is largely eliminated via hepatic metabolism by both phase I and phase II enzymes.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetamides / administration & dosage
  • Acetamides / metabolism
  • Acetamides / pharmacokinetics*
  • Administration, Oral
  • Aminophenols / administration & dosage
  • Aminophenols / metabolism
  • Aminophenols / pharmacokinetics*
  • Androgens* / blood
  • Androgens* / pharmacokinetics
  • Androgens* / urine
  • Animals
  • Area Under Curve
  • Biological Availability
  • Carbon Radioisotopes
  • Chromatography, Liquid / methods
  • Dogs
  • Dose-Response Relationship, Drug
  • Feces / chemistry
  • Half-Life
  • Injections, Intravenous
  • Liver / metabolism
  • Male
  • Mass Spectrometry / methods
  • Metabolic Clearance Rate
  • Rats
  • Rats, Sprague-Dawley
  • Species Specificity

Substances

  • Acetamides
  • Aminophenols
  • Androgens
  • Carbon Radioisotopes
  • andarine